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S100B is a reporter of blood-brain barrier (BBB) integrity which appears in blood when the BBB is breached. Circulating S100B derives from either extracranial sources or release into circulation by normal fluctuations in BBB integrity or pathologic BBB disruption (BBBD). Elevated S100B matches the clinical presence of indices of BBBD (gadolinium enhancement or albumin coefficient). After repeated sub-concussive episodes, serum S100B triggers an antigen-driven production of anti-S100B autoantibodies. We tested the hypothesis that the presence of S100B in extracranial tissue is due to peripheral cellular uptake of serum S100B by antigen presenting cells, which may induce the production of auto antibodies against S100B. To test this hypothesis, we used animal models of seizures, enrolled patients undergoing repeated BBBD, and collected serum samples from epileptic patients. We employed a broad array of techniques, including immunohistochemistry, RNA analysis, tracer injection and serum analysis. mRNA for S100B was segregated to barrier organs (testis, kidney and brain) but S100B protein was detected in immunocompetent cells in spleen, thymus and lymph nodes, in resident immune cells (Langerhans, satellite cells in heart muscle, etc.) and BBB endothelium. Uptake of labeled S100B by rat spleen CD4+ or CD8+ and CD86+ dendritic cells was exacerbated by pilocarpine-induced status epilepticus which is accompanied by BBBD. Clinical seizures were preceded by a surge of serum S100B. In patients undergoing repeated therapeutic BBBD, an autoimmune response against S100B was measured. In addition to its role in the central nervous system and its diagnostic value as a BBBD reporter, S100B may integrate blood-brain barrier disruption to the control of systemic immunity by a mechanism involving the activation of immune cells. We propose a scenario where extravasated S100B may trigger a pathologic autoimmune reaction linking systemic and CNS immune responses.

Background The prognostic value of serum biomarkers after out-of-hospital cardiac arrest (OHCA) depends on timing, but the physiological basis remains unclear. We investigated whether blood–brain barrier (BBB) integrity and biomarker-specific properties explain the time-dependent differences in prognostic performance. Methods This retrospective study included comatose adult OHCA survivors who underwent paired serum and cerebrospinal fluid (CSF) measurements of neuron-specific enolase (NSE; 47 kDa) and S100 calcium-binding protein B (S100B; 21 kDa) at 0 (H0), 24 (H24), 48 (H48), and 72 (H72) h after return of spontaneous circulation. BBB disruption was assessed using the CSF/serum albumin quotient (Q A ). Prognostic performance was assessed using AUC analysis for 6-month poor neurological outcome (Cerebral Performance Category 3–5). Results Among 111 patients (59% poor outcome), 646 serum and 620 CSF samples were analyzed. BBB disruption was more severe in the poor outcome group at all timepoints (all P  < 0.001), peaking at H24 (Q A 0.0282 [IQR 0.0150–0.120]) and remaining elevated at H72 (0.0228 [IQR 0.0147–0.0598]). In the poor outcome group, serum S100B levels peaked at H0 (0.80 ng/mL [IQR 0.39–2.81]) and declined despite a persistent elevation in CSF levels at or above the upper detection limit (≥ 30 ng/mL). Conversely, NSE levels progressively increased in both compartments, with serum and CSF levels increasing in parallel over time. Serum NSE concentrations showed a time-dependent improvement in prognostic accuracy, peaking at H72 (AUC 0.88), whereas S100B concentrations maintained stable performance across all timepoints (AUCs 0.79–0.85, all P  > 0.4). Notably, the prognostic performance of S100B remained relatively consistent regardless of BBB disruption severity, whereas NSE showed progressively improved predictive accuracy with increased BBB disruption. Across all timepoints, CSF biomarkers—particularly S100B and NSE—showed consistently higher AUCs than serum, suggesting superior prognostic utility. Conclusions Serum NSE levels closely reflect the degree of BBB disruption and CSF levels, while S100B exhibits a transient early-phase profile, with decreased serum detectability over time, even in the presence of sustained CSF elevation or severe BBB disruption. These findings highlight the importance of interpreting biomarker kinetics across compartments and timepoints rather than relying on molecular weight or BBB status alone.

Accurate assessment of traumatic brain injury (TBI) severity is essential for clinical management and outcome prediction. Traditional tools, like the Glasgow Coma Scale (GCS) and Maximum Abbreviated Injury Scale for head injuries (MAIS/Head), have limitations, particularly in cases involving sedation, complex injuries, or diffuse brain injuries. This study evaluates the diagnostic accuracy of plasma and salivary S100B levels as biomarkers for TBI severity, based on GCS and MAIS/Head, with emphasis on emergency settings. Multicenter prospective cohort study enrolled 57 adult patients with blunt TBI. TBI severity was assessed using GCS and MAIS/Head. Plasma and salivary S100B samples were collected 2–4h post-injury and measured via ELISA. Receiver operating characteristic (ROC) curves assessed S100B's discriminative capacity for TBI severity. Plasma and salivary S100B concentrations were higher in moderate and severe TBI cases. ROC analysis revealed strong discriminative performance for plasma (AUC = 0.87 and 0.83) and salivary S100B (AUC = 0.85 and 0.83), for GCS and MAIS/HEAD, respectively. Salivary S100B showed 100 % specificity for mild TBI and 100 % sensitivity for moderate TBI (MAIS/Head). Plasma S100B exhibited 100 % sensitivity for severe TBI (GCS ≤8). Both biomarkers did not distinguish between moderate and severe injuries. Plasma and salivary S100B levels effectively discriminate mild from severe TBI, complementing current clinical severity scales. Their use may support rapid decision-making in emergency departments, especially given the simplicity, non-invasiveness, and feasibility of salivary sampling. These findings support integrating S100B measurement into TBI management protocols to enhance clinical accuracy and patient outcomes. •Salivary and plasma S100B levels accurately identify mild and severe TBI cases.•Salivary S100B shows high specificity (86.7 %) for mild traumatic brain injury.•Plasma S100B demonstrates excellent sensitivity (100 %) for severe TBI detection.•Saliva collection emerges as a viable, non-invasive option in trauma settings.•S100B biomarker can complement clinical and anatomical TBI severity scales.

Circulating inflammatory markers are essential to human health and disease, and they are often dysregulated or malfunctioning in cancers as well as in cardiovascular, metabolic, immunologic and neuropsychiatric disorders. However, the genetic contribution to the physiological variation of levels of circulating inflammatory markers is largely unknown. Here we report the results of a genome-wide genetic study of blood concentration of ten cytokines, including the hitherto unexplored calcium-binding protein (S100B). The study leverages a unique sample of neonatal blood spots from 9,459 Danish subjects from the iPSYCH initiative. We estimate the SNP-heritability of marker levels as ranging from essentially zero for Erythropoietin (EPO) up to 73% for S100B. We identify and replicate 16 associated genomic regions (p < 5 x 10 −9 ), of which four are novel. We show that the associated variants map to enhancer elements, suggesting a possible transcriptional effect of genomic variants on the cytokine levels. The identification of the genetic architecture underlying the basic levels of cytokines is likely to prompt studies investigating the relationship between cytokines and complex disease. Our results also suggest that the genetic architecture of cytokines is stable from neonatal to adult life.

The calcium-binding S100B protein is concentrated in glial cells (including enteroglial cells) in the nervous system. Its conformation and amino acid composition are significantly conserved in different species; this characteristic suggests conserved biological role(s) for the protein. The biological activity is concentration-dependent: low physiological concentrations exert a neurotrophic effect, while high concentrations exert a proinflammatory/toxic role. The proinflammatory/toxic role of S100B currently attracts the scientific community’s primary attention, while the protein’s physiological action remains unraveled—yet remarkably interesting. This is now a topical issue due to the recently consolidated notion that S100B is a natural trophic nutrient available in breast milk and/or other aliments, possibly interacting with other body districts through its impact on microbiota. These recent data may offer novel clues to understanding the role of this challenging protein.

Serum biomarkers are associated with hemorrhagic transformation and brain edema after cerebral infarction. However, whether serum biomarkers predict hemorrhagic transformation in large vessel occlusion stroke even after mechanical thrombectomy, which has become widely used, remains uncertain. In this prospective study, we enrolled patients with large vessel occlusion stroke in the anterior circulation. We analyzed 91 patients with serum samples obtained on admission. The levels of matrix metalloproteinase-9 (MMP-9), amyloid precursor protein (APP) 770, endothelin-1, S100B, and claudin-5 were measured. We examined the association between serum biomarkers and hemorrhagic transformation within one week. Fifty-four patients underwent mechanical thrombectomy, and 17 patients developed relevant hemorrhagic transformation (rHT, defined as hemorrhagic changes ≥ hemorrhagic infarction type 2). Neither MMP-9 (no rHT: 46 ± 48 vs. rHT: 15 ± 4 ng/mL, P = 0.30), APP770 (80 ± 31 vs. 85 ± 8 ng/mL, P = 0.53), endothelin-1 (7.0 ± 25.7 vs. 2.0 ± 2.1 pg/mL, P = 0.42), S100B (13 ± 42 vs. 12 ± 15 pg/mL, P = 0.97), nor claudin-5 (1.7 ± 2.3 vs. 1.9 ± 1.5 ng/mL, P = 0.68) levels on admission were associated with subsequent rHT. When limited to patients who underwent mechanical thrombectomy, the level of claudin-5 was higher in patients with rHT than in those without (1.2 ± 1.0 vs. 2.1 ± 1.7 ng/mL, P = 0.0181). APP770 levels were marginally higher in patients with a midline shift ≥ 5 mm than in those without (79 ± 29 vs. 97 ± 41 ng/mL, P = 0.084). The predictive role of serum biomarkers has to be reexamined in the mechanical thrombectomy era because some previously reported serum biomarkers may not predict hemorrhagic transformation, whereas the level of APP770 may be useful for predicting brain edema.

S100 proteins assume a diversity of oligomeric states including large order self-assemblies, with an impact on protein structure and function. Previous work has uncovered that S100 proteins, including S100B, are prone to undergo β-aggregation under destabilizing conditions. This propensity is encoded in aggregation-prone regions (APR) mainly located in segments at the homodimer interface, and which are therefore mostly shielded from the solvent and from deleterious interactions, under native conditions. As in other systems, this characteristic may be used to develop peptides with pharmacological potential that selectively induce the aggregation of S100B through homotypic interactions with its APRs, resulting in functional inhibition through a loss of function. Here we report initial studies towards this goal. We applied the TANGO algorithm to identify specific APR segments in S100B helix IV and used this information to design and synthesize S100B-derived APR peptides. We then combined fluorescence spectroscopy, transmission electron microscopy, biolayer interferometry, and aggregation kinetics and determined that the synthetic peptides have strong aggregation propensity, interact with S100B, and may promote co-aggregation reactions. In this framework, we discuss the considerable potential of such APR-derived peptides to act pharmacologically over S100B in numerous physiological and pathological conditions, for instance as modifiers of the S100B interactome or as promoters of S100B inactivation by selective aggregation.

•Prognostic value of S100B in TBI, SAH and meningitis at 6 months following treatment.•Significant correlation between serum S100B and GOS in overall cohort, TBI and SAH (p<0.05).•Significant correlation between CSF S100B and GOS in SAH (p<0.05).•Serum S100B >0.7μg/l correlated with 100% mortality.•CSF S100B sensitive to small influences with EVD exchange causing significant increase (p<0.005). S100B has been proposed as a putative biochemical marker in determining the extent of brain injury and corresponding prognosis in neurotrauma. The aim of this study was to evaluate the prognostic value of S100B early concentrations in serum and cerebrospinal fluid (CSF) in traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH), to determine prognostically relevant threshold values and to evaluate fluctuation following EVD placement. In 102 patients (45 SAH and 57 TBI) under intensive care unit (ICU) treated between January 2011 and December 2012 with external ventricular drain (EVD) S100B measurements were performed simultaneously in serum and CSF during the first 5 days and before and after EVD exchange. Glasgow coma scale (GCS) was assessed on admission and Glasgow outcome scale (GOS) 6 months later. Peak S100B levels in CSF and serum were measured on the first day after admission and concentrations decreased during the ensuing days post injury gradually. CSF and serum S100B concentrations in TBI patients were significantly higher than in SAH (p<0.005). Both in TBI and SAH patients S100B concentrations in CSF and serum were significantly higher in patients with an unfavorable outcome (GOS 1–3) in comparison to patients with a good outcome (GOS 4–5). Correlation of S100B concentrations in serum and GOS score at 6 months was significant both in TBI and SAH (p<0.05). Serum S100B concentrations >0.7μg/l correlated with 100% mortality. Correlation between S100B in CSF and GOS was significant in SAH (p<0.05), whereas it was not significant in TBI. After EVD exchange (n=53) we found a significant increase of S100B concentration in CSF (p<0.005). Initial S100B levels have a limited prognostic value in neurotrauma with CSF concentrations being highly sensitive to smallest influences like EVD placement. However, high initial S100B levels of >0.7μg/dl in serum are associated with 100% mortality, which might help to guide therapy strategies in severe neurotrauma.

S100B(ββ) proteins are a family of multifunctional proteins that are present in several tissues and regulate a wide variety of cellular processes. Their altered expression levels have been associated with several human diseases, such as cancer, inflammatory disorders and neurodegenerative conditions, and hence are of interest as a therapeutic target and a biomarker. Small molecule inhibitors of S100B(ββ) have achieved limited success. Guided by the wealth of available experimental structures of S100B(ββ) in complex with diverse peptides from various protein interacting partners, we combine comparative structural analysis and molecular dynamics simulations to design a series of peptides and their analogues (stapled) as S100B(ββ) binders. The stapled peptides were subject to in silico mutagenesis experiments, resulting in optimized analogues that are predicted to bind to S100B(ββ) with high affinity, and were also modified with imaging agents to serve as diagnostic tools. These stapled peptides can serve as theranostics, which can be used to not only diagnose the levels of S100B(ββ) but also to disrupt the interactions of S100B(ββ) with partner proteins which drive disease progression, thus serving as novel therapeutics.

Schwann cells are an important cell source for regenerative therapy for neural disorders. We investigated the role of the transcription factor sex determining region Y (SRY)-box 10 (SOX10) in the proliferation and myelination of Schwann cells. SOX10 is predominantly expressed in rat sciatic nerve-derived Schwann cells and is induced shortly after birth. Among transcription factors known to be important for the differentiation of Schwann cells, SOX10 potently transactivates the S100B promoter. In cultures of Schwann cells, overexpressing SOX10 dramatically induces S100B expression, while knocking down SOX10 with shRNA suppresses S100B expression. Here, we identify three core response elements of SOX10 in the S100B promoter and intron 1 with a putative SOX motif. Knockdown of either SOX10 or S100B enhances the proliferation of Schwann cells. In addition, using dissociated cultures of dorsal root ganglia, we demonstrate that suppressing S100B with shRNA impairs myelination of Schwann cells. These results suggest that the SOX10-S100B signaling axis critically regulates Schwann cell proliferation and myelination, and therefore is a putative therapeutic target for neuronal disorders.